R E V I E W A R T I C L E Metabolic Liver Diseases Presenting as Acute Liver Failure in Children SEEMA A LAM AND BIKRANT BIHARI LAL From Department of Pediatric Hepatology, Institute of Liver and Biliary Sciences, New Delhi, India. Correspondence to: Prof Seema Alam, Professor and Head, Department of Pediatric Hepatology, Institute of Liver and Biliary Sciences, New Delhi 110 070, India. [email protected] Context: Suspecting metabolic liver disease in an infant or young child with acute liver failure, and a protocol-based workup for diagnosis is the need of the hour. Evidence acquisition: Data over the last 15 years was searched through Pubmed using the keywords “Metabolic liver disease” and “Acute liver failure” with emphasis on Indian perspective. Those published in English language where full text was retrievable were included for this review. Results: Metabolic liver diseases account for 13-43% cases of acute liver failure in infants and young children. Etiology remains indeterminate in very few cases of liver failure in studies where metabolic liver diseases were recognized in large proportion. Galactosemia, tyrosinemia and mitochondrial disorders in young children and Wilson’s disease in older children are commonly implicated. A high index of suspicion for metabolic liver diseases should be kept when there is strong family history of consanguinity, recurrent abortions or sibling deaths; and history of recurrent diarrhea, vomiting, failure to thrive or developmental delay. Simple dietary modifications and/or specific management can be life-saving if instituted promptly. Conclusion: A high index of suspicion in presence of red flag symptoms and signs, and a protocol-based approach helps in timely diagnosis and prompt administration of life- saving therapy. Keywords: Acute liver failure, Etiology, Infants, Liver Transplantation. Published online: June 01, 2016. PII:S097475591600005 nborn errors of metabolism, where hepatomegaly regardless of the presence or absence of clinical hepatic and/or abnormal liver functions form part of the encephalopathy. Neonatal liver failure is defined as clinical disease, are collectively referred to as “failure of the synthetic function of liver within 4 weeks of IMetabolic liver diseases (MLD). MLD can have birth’’ [10]. Presence of encephalopathy is not mandatory varied presentations in infants and children, most for defining acute liver failure in infants as it is often very common of them being: (i) organomegaly, (ii) difficult to recognize. Moreover, encephalopathy may be a encephalopathy due to hyperammonemia and/or primary very late event in the course of the disease [1,5]. We have lactic acidemia, (iii) pediatric acute liver failure (ALF), previously reported that average jaundice to (iv) cirrhosis with or without portal hypertension, and (v) encephalopathy interval is significantly higher in pediatric cholestatic liver disease. A high index of suspicion for ALF due to MLD group vis-à-vis other etiologies [1]. MLD is important as urgent intervention such as dietary Another important difference is that complete absence of manipulation or disease-specific treatment may be life- evidence of CLD cannot be kept as prerequisite, especially saving. The outcome of patients undergoing liver when the etiology is a suspected MLD [4]. MLD patients transplantation for MLD has improved considerably over may have variable degrees of liver damage before clinical the last decade. Moreover, it is important to establish the presentation, and overt signs and stigmata of chronic liver correct diagnosis, so that appropriate genetic counselling disease may be present. can be offered to the family. MLD merit special attention in differential diagnosis of pediatric ALF, especially in METABOLIC CAUSES OF ACUTE LIVER FAILURE infants and young children in whom they constitute 13- MLD are an important causes of pediatric ALF, 43% of all cases (Web Table I) [1-9]. especially in neonates, infants and young children. MLD The Pediatric ALF study group definition can be used account for 13-43% of acute liver failure in younger to define acute liver failure in infants and children [6]. The children, while accounting for only 5-20% of ALF in group enlists criteria for defining ALF as follows: (i) older children [1-9] (Web Table I). Studies which focus children with no known evidence of chronic liver disease on infants and young children have higher prevalence of (CLD), (ii) biochemical evidence of acute liver injury, and MLD as compared to the studies which include older (iii) hepatic-based coagulopathy defined as International children. The proportion of cases with indeterminate normalized ratio (INR) ≥1.5 not corrected by vitamin K in etiology are higher (38-53%)[4-6] in studies, where the the presence of clinical hepatic encephalopathy or INR ≥2 proportion of MLD cases is lower (13-19%). On the other INDIAN PEDIATRICS 695 VOLUME 53__AUGUST 15, 2016 ALAM & LAL METABOLIC LIVER DISEASES hand, the studies with higher prevalence (33-43%) of Children with MLD presenting as ALF tend to be MLD among pediatric ALF [1,3,7] had much smaller younger. A strong family history of consanguinity, proportion (13-18%) of cases remaining indeterminate. recurrent abortions, sibling deaths and previously Narkewicz, et al. [11] retrospectively analyzed the affected children are strong pointers to the possible workup of children labelled as indeterminate in pediatric etiology of MLD. History of recurrent diarrhea and ALF study group, and found that 54% of these children vomiting, failure to thrive and developmental delay are had not been screened for some common metabolic other indicators suggesting MLD [1,3]. Patients with disorders, before assigning them as indeterminate. In an MLD tend to have a longer jaundice to encephalopathy earlier Indian study, 4 children among 67 with fulminant interval. Neurological involvement in form of hypotonia, liver failure were reported to be non A, non E, but MLD myopathy, seizures, ophthalmoplegia, psychomotor was not reported [12]. However, this series included only dysfunction or presence of multisystem involvement one infant, and the definition used for ALF was different. should raise the suspicion of a mitochondrial depletion With advent of better diagnostic protocols, MLDs are syndrome [14]. more frequently diagnosed now [1]. A meticulous dietary history can help guide the Some of the authors have earlier listed neonatal clinician. Onset of liver dysfunction on milk feeds points hemochromatosis as a MLD. Being a gestation-associated towards diagnosis of galactosemia, whereas onset of alloimmune disorder, it has now been excluded from the symptoms after introduction of complementary foods list of MLDs. Galactosemia, tyrosinemia, mitochondrio- (containing fructose or sucrose) points towards hereditary pathies and fatty acid oxidation defect (FAOD) are the fructose intolerance that can also present in those receiving commonest metabolic diseases presenting as ALF in fructose in form of honey, syrups or formula milk infants. Wilson’s disease is the commonest MLD containing fructose or sorbitol. Aversion to sugars and presenting as ALF among older children, others being sweet foods in older children also suggests this disorder. mitochondriopathies, FAOD and urea cycle defects. Some MLD have their typical age of presentation and age- PATHOPHYSIOLOGY appropriate differential diagnosis should be considered (Table I). Encephalopathy is difficult to diagnose in In disorders such as galactosemia, tyrosinemia and Urea children and could be disproportionately more severe to cycle defects, the pathogenesis of MLD can be attributed the liver dysfunction in urea cycle defects and primary to a defect in the intermediary metabolic pathway leading lactic acidemias. Developmental delay, cardiomyopathy, to the accumulation of toxic metabolites (formed in one renal tubulopathy in a hypotonic child with convulsive of the preceding steps) which leads to liver failure. These disorder with or without treatment with valproic acid could conditions present after a symptom-free interval before be a setting for mitochondrial disorders. clinical signs of ‘intoxication’ appear. Acute attacks may be preceded by catabolic states, fever, intercurrent illnesses and specific food intake. Most of these disorders BOX 1 CLINICAL POINTERS OF METABOLIC LIVER DISEASES are treatable and require emergency removal of the toxin • Consanguinity, abortions and neonatal deaths by using special diets, extracorporeal procedures, drugs • SIDS and psychiatric illnesses or vitamins [13]. Another pathogenetic mechanism is an energy deficiency state. The mitochondrial energy • Recurrence in times of catabolic stress (fever, exercise, defects encompass the congenital lactic acidemias, prolonged fasting) respiratory chain disorders, pyruvate oxidation defects • Recurrent vomiting, diarrhea, failure to thrive , short and FAOD. Cytoplasmic energy defects include disorders stature, dysmorphic features, edema of glycolysis, glycogen metabolism, gluconeogenesis and • Seizures, early morning irritability, lethargy- the pentose phosphate pathways. The metabolic defects hypoglycemic symptoms with energy-deficient states present early and can even • Developmental delay, hypotonia and seizures, cataract, have prenatal onset. In lysosomal disorders (Wolman unusual odours, rickets, and renal tubulopathy disease and cholesteryl ester storage disorder), • Jaundice, hepatosplenomegaly and hepatic failure, peroxisomal disorders (Zellweger syndrome) and hypoglycemia,